Venting system for a mixing apparatus

ABSTRACT

A filter unit for a mixing apparatus includes a hydrophilic filter and a hydrophobic vent filter. The hydrophilic filter is configured to receive a fluid including a liquid and gas. The hydrophilic filter is further configured to sterilize the liquid. The hydrophobic vent filter is configured to receive the gas from the hydrophilic filter. The hydrophobic vent filter further includes a vent and a membrane configured to separate an interior of the filter unit from an exterior of the filter unit, the gas being vented from the filter unit by flowing across the membrane and out of the vent. In some embodiments, the filter unit further includes a defoaming device configured to receive gas, foam comprised the liquid containing trapped gas, and some of the liquid from the hydrophilic filter and is further configured to release at least some of the gas from the foam.

CROSS-REFERENCE TO RELATED APPLICATION

This Application claims priority to U.S. Provisional Patent ApplicationNo. 62/725,717, filed Aug. 31, 2018, which application is incorporatedherein by reference in its entirety.

BACKGROUND

Embodiments of the present technology generally relate to components foran automated method and apparatus for mixing at least one material withat least one fluid. More particularly, embodiments of the presenttechnology relate to sterilization and/or filtration components for anautomated method and apparatus specifically adapted for reconstitutingdry ingredients into bioprocess solutions.

A bioprocess is a process that uses living cells or their components toobtain desired products. Bioprocesses often require the use of varioussolutions. For example, the initial steps in a bioprocess may involvecell culturing, and cell culturing often requires the use of cellculture media to successfully cultivate new cells. Later steps in abioprocess may then require the use of various buffer solutions as partof a product purification process.

Bioprocess solutions are often hydrated from dry ingredients immediatelybefore use either in large stainless steel tanks or in single-use mixingdevices. The typical process is time-consuming, expensive, and adds nodirect value to the desired product.

While the basic cell culture methods have not changed appreciably overthe years, the volumes of cell cultures continue to increasedramatically, thereby changing the requirements for media preparation.Not only are more research laboratories, pharmaceutical, andbiotechnology companies employing cell culture methods, but they areoften doing so on a very large scale. A biotechnology company mayconsume many thousands of liters of liquid media a day and employ largenumbers of manufacturing technicians and scientists to produceantibodies, growth factors, or recombinant proteins from cell culturefor commercial use. The present disclosure provides an automated systemand method for employing an in-line mixing device to prepare bioprocesssolutions that can help reduce the required time, labor, risk of errorand risk of contamination in these processes while also improvingreliability and consistency.

Using an in-line mixing device requires venting gas, such as air, duringa reconstitution process used, for example, to prepare a bioprocesssolution. If not vented, air may displace the solution beingreconstituted within the mixing device. Furthermore, air present in anin-line mixing device may not pass through filtration membranes (e.g.,sterilizing hydrophilic membranes), causing the flow of the aqueousliquid in the mixing device to slow or even stop.

SUMMARY

Generally, embodiments described herein relate to components forautomated methods and apparatuses for preparing dry ingredients intoliquid solutions (e.g., preparing powdered bioprocess media into liquidbioprocess media). As discussed further below, dry ingredients tend torequire less storage space than reconstituted, liquid solutions, havelonger shelf lives, be less expensive, and require less shipping andhandling time than prepackaged liquid solutions. Thus, when liquidsolutions are needed, it is advantageous to utilize automated methodsand apparatuses designed to make the preparation of liquid solutionsfrom dry ingredients simple, straightforward, and repeatable, ratherthan purchase prepackaged liquid solutions. Accordingly, the technologyaccording to some embodiments relates to components for an automatedmethod for mixing dry ingredients (e.g., a powdered media) into a fluid,such as cell culture media or buffers. More particularly, someembodiments of the present technology relate to sterilization and/orfiltration components for a mixing apparatus usable via an automatedmethod, where both the automated method and the mixing apparatus areadapted for reconstituting dry ingredients into liquids in predeterminedunit volume amounts.

A variety of dry ingredients may be reconstituted into liquid solutionsusing the present technology. For example, as used herein, dryingredients may refer to powdered cell culture media, dry powder media,dry buffer powder, granulated media, dry salts, dry chemicals, drycomponents, dry materials, and unhydrated ingredients.

One embodiment relates to a filter unit for a mixing apparatus. Thefilter unit includes a hydrophilic filter and a hydrophobic vent filter.The hydrophilic filter is configured to receive a fluid including aliquid and gas. The hydrophilic filter is further configured tosterilize the liquid. The hydrophobic vent filter is configured toreceive the gas from the hydrophilic filter. The hydrophobic vent filterfurther includes a vent and a membrane configured to separate aninterior of the filter unit from an exterior of the filter unit, the gasbeing vented from the filter unit by flowing across the membrane and outof the vent.

Another embodiment relates to a filter unit for a mixing apparatus. Thefilter unit includes a hydrophilic filter, a defoaming device, and ahydrophobic vent filter. The hydrophilic filter is configured to receivea fluid including a liquid, gas, and foam comprised of the liquidcontaining trapped gas. The hydrophilic filter is further configured tosterilize the liquid. The defoaming device is configured to receive thegas, the foam, and some of the liquid from the hydrophilic filter. Thedefoaming device is further configured to release at least some of thegas from the foam. The hydrophobic vent filter is configured to receivethe gas from the defoaming device. The hydrophobic vent filter furtherincludes a vent and a membrane configured to separate an interior of thefilter unit from an exterior of the filter unit, the gas being ventedfrom the filter unit by flowing across the membrane and out of the vent.

Another embodiment relates to a method of filtering a solution. Themethod includes receiving, at a filter unit including of a hydrophilicfilter, a defoaming device, and a hydrophobic vent filter, a fluidincluding a liquid, gas, and foam comprised of the liquid containingtrapped gas; directing the gas and foam to the defoaming device, whereinthe defoaming device is configured to release at least some of the gasfrom the foam; and venting the gas across a membrane and out of a ventof the hydrophobic vent filter, the membrane configured to separate aninterior of the filter unit from an exterior of the filter unit. Themethod further includes sterilizing the liquid by the hydrophilic filterand evacuating the sterilized liquid from the filter unit.

BRIEF DESCRIPTION OF THE DRAWINGS

The above-mentioned features, as well as other features, aspects, andadvantages, of the present technology will now be described inconnection with various embodiments, in reference to the accompanyingdrawings. The illustrated embodiments, however, are merely examples andare not intended to limit the invention.

FIG. 1 is a schematic representation of a mixing apparatus including afilter unit for reconstituting a powder, such as a powdered bioprocessmedia, according to an exemplary embodiment.

FIG. 2 is a detailed schematic representation of the filter unit of FIG.1, according to an exemplary embodiment.

FIG. 3 is a perspective view of a filter element of the filter unit,according to an exemplary embodiment.

FIG. 4 is a cross-sectional view of the filter element of FIG. 3,according to an exemplary embodiment.

FIG. 5 is a detailed schematic representation of the filter unit of FIG.1 depicting the flow of fluids within the filter, according to anexemplary embodiment.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part of the present disclosure. Inthe drawings, similar symbols typically identify similar components,unless context dictates otherwise. The illustrative embodimentsdescribed in the detailed description, drawings, and claims are notmeant to be limiting. The detailed description is intended as adescription of exemplary embodiments and is not intended to representthe only embodiments that may be practiced. The term “exemplary,” asused herein, means “serving as an example, instance, or illustration”and should not necessarily be construed as preferred or advantageousover other embodiments. Other embodiments may be utilized, and otherchanges may be made, without departing from the spirit or scope of thesubject matter presented herein. It will be readily understood that theaspects of the present disclosure, as generally described herein andillustrated in the Figures, can be arranged, substituted, combined, anddesigned in a wide variety of different configurations, all of which areexplicitly contemplated and form part of this disclosure.

Embodiments described herein generally relate to filtration and/orsterilization components for devices/apparatuses, systems, and methodsused in the preparation of solutions from dry ingredients, for example,media for cell culture from dry powdered cell culture media or buffersolutions from dry buffer powder. One or more of the providedembodiments may overcome one or more of the drawbacks, limitations, ordeficiencies that exist in the art with respect to reconstitutingsolutions, particularly with respect to reconstituting cell culturemedia in a dry format, including dry powder media. For example, in someembodiments described herein, components may facilitate the venting ofgas, such as air, from an apparatus used to reconstitute a powder suchthat the reconstitution occurs more efficiently and produces a solution,for example, that does not contain unwanted foam or trapped gas, such asair.

The present disclosure makes reference to the systems and methodsdescribed herein in the context of preparing liquid cell culture mediafrom powdered cell culture media. However, it should be understood thatthe systems and methods described herein can be adapted to preparingother types of solutions. For example, the systems and methods describedherein may be used to prepare buffers for chromatography and downstreamprocessing of biopharmaceutical bulk drug substances. As anotherexample, the systems and methods described herein may be used to preparevarious “bioprocess solutions,” or solutions that are used in processesof using living cells or their components to obtain desired products.Moreover, it is contemplated that the systems and methods describedherein may be adapted for a number of broader commercial or industrialapplications. As an example, many liquid pharmaceuticals are prepared inthe hospital pharmacy with some frequency and quantity. Salinesolutions, alimentary preparations, imaging reagents, dyes,sterilization solutions, and anesthetics are reconstituted as liquids.Additional alternative applications include, but are not limited to,preparation of pesticides, fertilizers, and any of a variety ofbeverages commonly prepared from powder (e.g., milk, iced tea, etc.),all of which could be reconstituted using embodiments of the systems andmethods described herein. In this regard, dry ingredients that may bereconstituted using the present systems and methods are not limited topowdered cell culture media and may include dry powder media, dry bufferpowder, granulated media, dry salts, dry chemicals, dry components, drymaterials, and unhydrated ingredients.

FIG. 1 is an overall system view of one embodiment of a mixing apparatus10. Preferably, the mixing apparatus 10 is made of materials that areappropriate for the cell culture environment, such as non-toxic, medicalgrade plastics or other non-toxic materials that will not contaminatethe media. The mixing apparatus 10 includes a first mixing chamber 12, asecond mixing chamber 14, and a filter unit 16 connected together withvarious lengths of tubing 18 (e.g., flexible hoses). The tubing furtherincludes various valves 20 provided therein for selectively allowing(e.g., when the valve is in an open position) and stopping (e.g., whenthe valve is in a closed position) the flow of fluids through thevalves. In an exemplary embodiment, the valves are pinch valves, thoughin other embodiments, the valves may be or include other types ofvalves, such as ball valves. In various embodiments, the mixingapparatus 10 is designed for reconstitution of powdered cell culturemedia into liquid media. For example, the mixing apparatus 10 may be asingle use apparatus with necessary media components (e.g., powderedcell culture media, sodium bicarbonate, etc.) prepackaged therein.However, those of skill in the art will appreciate that the mixingapparatus 10 may also be used to reconstitute other forms of undissolvedcell culture media (e.g., granulated cell culture media), preparebioprocessing buffers from a dry format, or more generally reconstituteliquids from powders.

To begin with, in various embodiments, the first mixing chamber 12contains dry powder media to be reconstituted into liquid media. Forexample, the first mixing chamber 12 may be provided with a premeasuredamount of dry powder media. In some embodiments, the first mixingchamber 12 may be prepackaged with the premeasured amount of dry powdermedia already therein. Additionally, in various embodiments, the firstmixing chamber 12 is designed to facilitate mixing of the media withpurified water and/or with other powders or liquids, such as dissolvedsodium bicarbonate or a supplement. For example, the first mixingchamber 12 may include a top and/or bottom cone coupled to the topand/or bottom end, respectively, of the first mixing chamber 12 tofacilitate the creation of a swirling vortex motion as fluid enters thefirst mixing chamber 12. The swirling vortex motion helps facilitate themixing of the dry powder media, the purified water, dissolved sodiumbicarbonate, a supplement, etc. Various configurations and embodimentsof the first mixing chamber 12 are described in U.S. application Ser.No. 15/087,826 titled “Media Mixing Chamber,” filed on Mar. 31, 2016,and hereby incorporated herein in its entirety.

The first mixing chamber 12 also includes various ports whereby fluidsmay flow into and out of the first mixing chamber 12, such as a topport, an upper port, and a lower port. In exemplary embodiments, atleast some of the ports may be positioned on the first mixing chamber 12such that fluids enter the first mixing chamber 12 at substantially atangential angle to an inner wall of the first mixing chamber, which mayfurther facilitate the mixing of various media components in the firstmixing chamber. Additionally, the first mixing chamber 12 is connectedvia at least some of the ports with tubing 18 to various inlets 22,which may in turn be connected to various fluid sources for thereconstitution process, such as water, supplements for cell media, andcompressed air to flush out remaining media from the apparatus 10 oncethe reconstitution process is completed.

In various embodiments, the second mixing chamber 14 contains anadditive to the cell culture media. In an exemplary embodiment, thesecond mixing chamber 14 contains sodium bicarbonate powder, and thesecond mixing chamber 14 is designed to facilitate mixing of the sodiumbicarbonate with purified water. Additionally, the second mixing chamber14 may be prepackaged with a premeasured amount of sodium bicarbonatetherein. In some embodiments, the second mixing chamber 14 is configuredsimilarly to the first mixing chamber 12 (e.g., including a top and/orbottom cone coupled to the top and/or bottom end, respectively, of thesecond mixing chamber 14 to facilitate the creation of a swirling vortexmotion as fluid enters the second mixing chamber 14). In otherembodiments, the second mixing chamber 14 is configured differently fromthe first mixing chamber 12. Various configurations and embodiments ofthe second mixing chamber 14 are also described in U.S. application Ser.No. 15/087,826 titled “Media Mixing Chamber,” filed on Mar. 31, 2016,which as noted above is incorporated herein in its entirety.

Similar to the first mixing chamber 12, the second mixing chamber 14includes various ports whereby fluids may flow into and out of thesecond mixing chamber, such as a top port and a lower port.Additionally, at least some of the ports may also be positioned on thesecond mixing chamber 14 such that fluids enter the second mixingchamber 14 at substantially a tangential angle to an inner wall of themixing chamber. The second mixing chamber 14 is further connected via atleast some of the ports with tubing 18 to various of the inlets 22, suchas an inlet connected to a water source. Moreover, as shown in FIG. 1,the first mixing chamber 12 and the second mixing chamber 14 may beconnected to each other via their respective ports with tubing 18.

The apparatus 10 also includes the filter unit 16 positioned before anoutlet 24 for the apparatus 10. The filter unit 16 is configured tofilter reconstituted solution flowing into the filter unit 16. Forexample, in the embodiment shown in FIG. 1, fluid may flow into thefilter unit 16 from the first mixing chamber 12 and/or a water source.The filter unit 16 may be further configured to sterilize the solutionflowing into the filter unit 16. Additionally, as described in furtherdetail below, the filter is configured to remove air or other gas fromthe solution. Once the reconstituted solution has been filtered and/orsterilized by the filter unit 16, the solution flows out of theapparatus 10 via the outlet 24 and, for example, is directed into asterile storage container.

Additionally, in various embodiments, the mixing apparatus 10 mayinclude various sensors for taking measurements in the mixing apparatus10. These sensors may include, for example, pressure sensors (e.g., fordetecting water pressure within the apparatus 10), conductivity sensors(e.g., for detecting the conductivity, and thus the concentration, ofsolutions in the apparatus 10), cumulative volume sensors, such as arotary flow meter, (e.g., for detecting a volume and flow rate of fluidconsumed in the mixing process), pH sensors (e.g., for detecting the pHof solutions in the apparatus 10), viscometers (e.g., for measuring theviscosity of fluids in the apparatus 10), and so on. For example, in theembodiment of FIG. 1, the apparatus 10 includes sensors 26 positioned asshown in the tubing 18. These sensors 26 may include a pressor sensorconfigured to measure the pressure of fluids flowing into the filterunit 16 (e.g., to ensure that the filter unit 16 backpressure does notbecome too high); a conductivity sensor configured to measure theconductivity of the solution flowing into the filter unit 16, therebyindirectly measuring the concentration of the solution flowing into thefilter unit 16 and ultimately out of the apparatus 10; and a volumesensor configured to measure the volume and flow rate of water consumedduring the mixing process.

In various embodiments, the powdered media are also mixed into liquidmedia in the mixing apparatus 10 through an automated method. Forexample, a computing system may control the opening and closing ofvalves, as well as fluid sources used during the automated method (e.g.,a water source, a compressed air source, a supplement source), tocontrol the mixing of the powdered media. The computing system may openand/or close valves and component sources in response to a variety oftriggers. For example, the computing system may receive measurementsfrom the mixing apparatus 10 related to the mixing process (e.g., from apressure sensor, a conductivity sensor, and a volume sensor). Thecomputing system may then open and/or close valves and/or fluid sourcesin response to receiving measurements of certain levels, below or abovecertain levels, within certain ranges, etc. As another example, thecomputing system may open and/or close valves and/or fluid sources inresponse to certain amounts of elapsed time.

Using the mixing apparatus 10 to prepare liquid media from dry powderedmedia through an automated method is an improvement over the currentfield, as it allows for easy and efficient liquid media preparation.Additionally, having programming logic (e.g., implemented by aprocessing circuit executing instructions stored on non-transitorymachine readable media as part of a computing system) controlling theautomated method makes the preparation of liquid media from dry powderedmedia repeatable and consistent. Additional detail on variousconfigurations and embodiments of the mixing apparatus 10 and theautomated method used with the mixing apparatus 10 are described in U.S.patent application Ser. No. 16/017,014, titled “Automated Method andApparatus for Preparing Bioprocess Solutions,” filed on Jun. 25, 2018,and hereby incorporated herein in its entirety.

Hydrating and filtering a powder, such as powdered cell culture media,in a closed or substantially closed system (e.g., mixing apparatus 10)requires venting gas, such as air. Air will not pass through a typicalsterilizing hydrophilic membrane of a filter (e.g., filter unit 16) atnormal operating pressures for sterile filtration of aqueous liquids. Ifthe air is not removed by venting, the filter flow will be reduced andeventually stop as air displaces aqueous liquid on the upstream side ofthe filter. Additionally, the dry areas of the hydrophilic membrane willnot allow aqueous liquid to pass through.

As such, to allow for efficient flow of liquid through a mixingapparatus, the filter for the apparatus needs an air vent. However, thevent must be selectively permeable for outbound air and not for inboundmicroorganisms, which could contaminate the solution in the apparatusand compromise the closed system. Additionally, the air vent shouldprevent discharge of aqueous liquid being mixed in the mixing apparatus.

In such situations, it has been determined that employing asemipermeable hydrophobic membrane with sufficiently small pores (e.g.,0.2 μm or less) can selectively allow air or other gas to vent andprevent both in-bound microbial contamination and discharge of aqueousliquid as long as the membrane is substantially dry and free of foam.However, the hydration of a powder, such as powdered cell culture media,produces a mixture of liquid and air that can generate very small gasbubbles and foam (e.g., solution liquid containing trapped air) thatinhibit the venting of air through a hydrophobic membrane. The foam andbubbles wet the membrane, and wetted areas of the hydrophobic membranewill not allow air to pass through. Reduction of the vent flow ratecauses accumulation of air in the system that, as noted above, displacesthe aqueous liquid on the upstream side of the hydrophilic filter andultimately reduces flow rates of the aqueous liquid filtrate. As such,it has further been determined that sufficient air venting can besustained by employing a defoaming device immediately upstream of thehydrophobic vent filter. By helping to break small air bubbles and foam,the device effectively allows separation of aqueous liquid from air andcan prevent wetting of the hydrophobic vent filter.

FIG. 2 is a detailed view of the filter unit 16 incorporating theseadvantageous features. In various embodiments, the filter unit 16includes a hydrophilic filter 100, a defoaming device 102, and ahydrophobic vent filter 104. The hydrophilic filter 100 is a sterilizingfilter and includes a membrane for sterilizing incoming solution. Insome embodiments, the hydrophilic filter 100 includes a hollow,cylindrical filter element 100 b (not seen in FIG. 2). FIG. 3 and thecross-sectional view of FIG. 4 depict cylindrical filter element 100 b,including a pleated membrane 100 c (e.g., at the outer surface of thefilter element). As shown in FIG. 5, hydrophilic filter 100 includescylindrical filter element 100 b that fits into a cylindrical filtercapsule 100 a such that there is space between the filter element 100 band the filter capsule 100 a. The cylindrical filter element 100 bincludes membrane 100 c that sterilizes solution coming into thehydrophilic filter 100. For example, the aqueous liquid entering thehydrophilic filter 100 passes through this membrane 100 c of thecylindrical filter element 100 b at 5-15 L/min. Accordingly, in variousimplementations, the solution enters the hydrophilic filter 100 via aninlet 106 into the space between the filter capsule 100 a and the filterelement 100 b, is sterilized by passing through the membrane 100 c ofthe filter element 100 b into the hollow center of the filter element100 b, and is evacuated from the hydrophilic filter 100 via an outlet108. In various embodiments, the hydrophilic filter element 100 b is atleast partially composed of a hydrophilic material such aspolyethersulfone (“PES”).

Referring again to FIG. 2, the defoaming device 102 contains a defoamingsubstance 110 configured to break up small air bubbles and foam in thesolution to release air trapped therein. For example, in someembodiments, the defoaming substance may be steel wool or stainlesssteel shavings. Accordingly, the defoaming device 102 is configured toreceive at least some of the solution from the hydrophilic filter 100,including any foam and air mixed in with the solution, and break upbubbles and foam in the solution to release air from the solution. As anillustration, the defoaming substance 110 may be configured to break upthe air bubbles and foam through a combination of kinetic forces of theflowing solution and the structure of the defoaming substance 110.

The hydrophobic vent filter 104 is configured to vent air or other gasfrom the solution being mixed in the apparatus 10. For example, in someembodiments, the hydrophobic vent filter 104 may vent up to 50 L of airduring a mixing process. As shown in FIG. 5, in some embodiments, thehydrophobic vent filter 104 includes a cylindrical filter element 104 b(including a membrane at an outer surface of the filter element 104 b,similar to filter element 100 b and membrane 100 c) that fits into acylindrical filter capsule 104 a. Thus, in various implementations, air(and any solution incidentally pushed or sprayed into the hydrophobicvent filter 104) from the hydrophilic filter 100 enters the hydrophobicvent filter 104 into the space between the filter capsule 104 a and thefilter element 104 b. The air then flows through the membrane of filterelement 104 b into the hollow center inside the filter element 104 b andthen out of the hydrophobic vent filter 104, and thus the apparatus 10,through a vent 112 positioned on the top of the hydrophobic vent filter104 (e.g., incorporated as part of the filter capsule 104 a).Additionally, the membrane 104 c separates an interior of the filterunit 16 from an exterior of the filter unit 16 such that, for example,microbes and unwanted particulates do not enter the apparatus 10 andcompromise the closed system of the apparatus 10. In variousembodiments, the hydrophobic vent filter element 104 b is at leastpartially composed of a hydrophobic material such aspolytetrafluoroethylene (“PTFE”) or polyvinylidene fluoride (“PVDF”).

FIG. 5 illustrates the flow of solution and air through the filter unit16. In the embodiment of FIG. 5, the flow of unsterilized solution isillustrated by solid arrows 200, the flow of air or other gas isillustrated by dotted arrows 202, and the flow of sterilized solution isillustrated by dotted arrows 204. Additionally, FIG. 5 illustrates boththe filter capsule 100 a, 104 a and the filter element 100 b, 104 b foreach of the hydrophilic filter 100 and the hydrophobic vent filter 104.As shown, the hydrophilic filter 100 includes hydrophilic filter capsule100 a and hydrophilic filter element 100 b, and the hydrophobic ventfilter 104 includes hydrophobic filter capsule 104 a and a hydrophobicfilter element 104 b.

As shown in FIG. 5, unsterilized solution 200 and air or other gas 202enters into the hydrophilic filter 100 through the inlet 106. Theunsterilized solution 200 fills the space between the hydrophilic filtercapsule 100 a and the hydrophilic filter element 100 b. The unsterilizedsolution 200 passes through the membrane 100 c of the hydrophilic filterelement 100 b (e.g., at a rate of 5-15 L/min), thereby becomingsterilized, and into the hollow center within the hydrophilic filterelement 100 b. The sterilized solution 204 is then evacuated out of thefilter unit 16 by flowing through the outlet 108 (e.g., coupled to anoutlet port on the hydrophilic filter capsule 100 a through which thesterilized solution is evacuated from the hydrophilic filter 100). Thesterilized filtrate 204 may then be collected in a sterile vessel and,for example, used as part of a bioprocess.

Additionally, the unsterilized solution 200 and any air or other gas 202can flow from the hydrophilic filter 100 into the defoaming device 102.In practice, for example, the air and any bubbles or foam may rise fromthe unsterilized solution 200 in the hydrophilic filter 100 into thedefoaming device 102. The defoaming substance 110 in the defoamingdevice 102 breaks up bubbles and foam in the solution, thereby releasingthe air 202 trapped within and allowing the unsterilized solution toflow back into the hydrophilic filter 100.

The air or other gas 202 then flows into the hydrophobic vent filter 104(e.g., along with small amounts of unsterilized solution also pushed orsprayed into the hydrophobic vent filter 104). As shown in FIG. 5, theair 202 flows into the space between the hydrophobic filter capsule 104a and the hydrophobic filter element 104 b. The air flows through themembrane 104 c of the hydrophobic filter element 104 b into the hollowcenter of the hydrophobic filter element 104 b. The membrane (e.g., a0.2 μm barrier) of the hydrophobic filter element 104 b preventsbacteria and other microbes from entering the apparatus 10. The air thenflows out of the center of the hydrophobic filter element 104 b andthrough the vent 112, thereby leaving the apparatus 10.

In this way, the filter unit 16 is able to separate and vent air frommixed solution, as well as sterilize the solution, while preserving theclosed system of the mixing apparatus 10. The filter unit 16 composed ofthe hydrophilic filter 100, defoaming device 102, and hydrophobic ventfilter 104 thus provides the technical advantages discussed above. Inaddition, in some embodiments, the above-described configuration of thefilter unit 16 represents an unusual approach for sterilization ofsolution and venting of air during a mixing process because manyhydrophobic filters may be recommended for performance in dry conditionsonly. For example, while hydrophobic filters may be tested to measurethe minimum “breakthrough pressure” of water, it may be recommended thatmany hydrophobic filters do not get wet because moisture can potentiallyaffect the performance of the hydrophobic filters. By contrast, in thefilter unit 16 described above, while the hydrophobic vent filter 104 isnot directly configured to receive the flow of unsterilized solution,the hydrophobic vent filter 104 may still contact some of theunsterilized solution from the defoaming device 102 (e.g., because theunsterilized solution is sprayed into the hydrophobic vent filter 104due to kinetic forces of the flow of the unsterilized solution). Assuch, the above-described configuration of the filter unit 16 may beunusual in filtration systems. However, this configuration may allow theapparatus 10 to effectively vent air, as well as separate trapped airfrom mixed solution, while maintaining the solution inside the apparatus10 and maintaining a closed system as described above. Accordingly, thisconfiguration may be advantageous for many applications of the apparatus10.

Alternatively, in some embodiments, the filter unit 16 may not includethe defoaming device 102. Instead, the hydrophilic filter 100 may bedirectly connected to the hydrophobic vent filter 104 (not shown). Insuch embodiments, the unsterilized solution may be more likely to sprayor flow into the hydrophobic vent filter 104, thus increasing theunexpectedness of using such a configuration. However, thisconfiguration may allow solution to be effectively sterilized and airvented, for example, in situations where foaming is of less concern orless of an issue.

It should also be understood that, in some embodiments, the filter unit16 may be arranged in other configurations different from the filterunit 16 shown in FIGS. 2 and 3. For example, in some embodiments, nosterilization of the solution being mixed in the apparatus 10 may benecessary. As such, the filter unit 16 may include the defoaming device102 and the hydrophobic vent filter 104 but not the hydrophilic filter100. Alternatively, in other embodiments, the filter unit 16 may includedifferent or additional components, such as multiple vents.Additionally, it should be understood that in other embodiments, theapparatus 10 may be configured differently than the apparatus 10 shownin FIG. 1. For example, in some embodiments, the filter unit 16 may belocated in a different section of the apparatus 10.

Furthermore, while the above embodiments are described with reference tothe reconstitution of powdered cell culture media, it should beunderstood that embodiments of the mixing apparatus 10 and the filterunit 16 may be used with automated method embodiments to reconstitute avariety of dry ingredients into liquids, such as a variety of bioprocesspowders into bioprocess solutions. It is further contemplated that theliquid solvents employed can be water, alcohols, or other organics. Thesolubility characteristics, the solvent to be used, the amount required,and the chemical interactions between the solvent and the reconstitutedchemicals will serve to provide guidelines for the configuration of themixing apparatus 10 and/or the filter unit 16, as well as any automatedmethods used to reconstitute the powders using the apparatus 10.

The filter unit 16 may comprise nylon or cellulose acetate.Additionally, for a media product, the membrane(s) used in the filterunit 16 may be 0.2 μm filters, though it is contemplated that otherfilter sizes could be chosen for certain functions. For example, thepreparation of electrophoretic buffers requires clean, but notnecessarily sterile solutions, and a 0.45 μ filter would be adequate.Similarly, the preparation of more viscous solutions may necessitate awider pore size. In short, the membrane(s) used in the filter unit 16can be of any desired size, volume, pore size, and so forth.

It will be appreciated by those skilled in the art that variousmodifications and changes may be made without departing from the scopeof the described technology. Such modifications and changes are intendedto fall within the scope of the embodiments, as defined by the appendedclaims. It will also be appreciated by those of skill in the art thatparts included in one embodiment are interchangeable with otherembodiments; one or more parts from a depicted embodiment can beincluded with other depicted embodiments in any combination. Forexample, any of the various components described herein and/or depictedin the Figures may be combined, interchanged, or excluded from otherembodiments.

The embodiments herein have been described with reference to drawings.The drawings illustrate certain details of specific embodiments thatimplement the systems and methods described herein. However, describingthe embodiments with drawing should not be construed as imposing on thedisclosure any limitations that may be present in the drawings.

With respect to the use of any plural and/or singular terms herein,those having skill in the art can translate from the plural to thesingular and/or from the singular to the plural as is appropriate to thecontext and/or application. The various singular/plural permutations maybe expressly set forth herein for sake of clarity.

It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims, are generallyintended as “open” terms (e.g., the term “including” should beinterpreted as “including but not limited to,” the terms “comprising”and “having” should, respectively, be interpreted as “comprising atleast” and “having at least,” the term “includes” should be interpretedas “includes but it not limited to,” etc.). It will be furtherunderstood by those within the art that if a specific number of anintroduced claim recitation is intended, such an intent will beexplicitly recited in the claim, and in the absence of such recitationno such intent is present. For example, as an aid to understanding, thefollowing appended claims may contain usage of the introductory phrases“at least one” and “one or more” to introduce claim recitations.However, the use of such phrases should not be constructed to imply thatthe introduction of a claim recitation by the indefinite articles “a” or“an” limits any particular claim containing such introduced claimrecitation to embodiments containing only one such recitation, even whenthe same claim includes the introductory phrases “one or more” or “atleast one” and indefinite articles such as “a” or “an.” In general, “a”and/or “an” should be interpreted to mean “at least one” or “one ormore”; the same holds true for the use of definite articles used tointroduce claim recitations.

Furthermore, in those instances where a convention analogous to “atleast one of A, B, and C, etc.” is used, in general, such a constructionis intended in the sense one having skill in the art would understandthe convention (e.g., “a system having at least one of A, B, and C”would include but not be limited to systems that have A alone, B alone,C alone, A and B together, A and C together, B and C together, and/or A,B, and C together, etc.). In those instances where a conventionanalogous to “at least one of A, B, or C, etc.” is used, in general,such a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, or C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibility of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

For the purpose of this disclosure, the term “coupled” means the joiningof two members directly or indirectly to one another. Such joining maybe stationary or moveable in nature. Such joining may be achieved withthe two members or the two members and any additional intermediatemembers being integrally formed as a single unitary body with oneanother, or with the two members or the two members and any additionalintermediate members being attached to one another. Such joining may bepermanent in nature or may be removable or releasable in nature.

The technology discussed herein has numerous applications and whileparticular embodiments of the technology have been described in detail,it will be apparent to those skilled in the art that the disclosedembodiments may be modified given the design considerations discussedherein. Therefore, the foregoing description is to be consideredexemplary rather than limiting, and the true scope of the invention isthat defined in the following claims.

What is claimed is:
 1. A filter unit for a mixing apparatus comprising:a hydrophilic filter configured to receive a fluid including a liquidand gas, the hydrophilic filter further configured to sterilize theliquid; and a hydrophobic vent filter configured to receive the gas fromthe hydrophilic filter, the hydrophobic vent filter further comprising avent and a membrane configured to separate an interior of the filterunit from an exterior of the filter unit, the gas being vented from thefilter unit by flowing across the membrane and out of the vent.
 2. Thefilter unit of claim 1, wherein the hydrophobic vent filter isconfigured to receive some of the liquid from the hydrophilic filter. 3.The filter unit of claim 1, wherein the hydrophobic vent filter is atleast partially composed of at least one of polytetrafluoroethylene orpolyvinylidene fluoride.
 4. The filter unit of claim 1, wherein thehydrophilic filter is at least partially composed of a polyethersulfone.5. The filter unit of claim 1, wherein the hydrophobic vent filterfurther comprises a hollow cylindrical filter element disposed within acylindrical filter capsule, the filter capsule comprising the vent andthe filter element comprising the membrane; and wherein the filterelement is coupled to the filter capsule such that gas is vented fromthe filter unit by flowing across the membrane into a hollow center ofthe filter element and out of the vent.
 6. The filter unit of claim 1,wherein the hydrophilic filter comprises a hollow cylindrical filterelement disposed within a cylindrical filter capsule, the filter capsulecomprising an outlet port and the filter element comprising a secondmembrane configured to sterilize the liquid; and wherein the filterelement is coupled to the filter capsule such that the liquid isevacuated from the filter unit by flowing across the second membraneinto a hollow center of the filter element and out of the outlet port.7. A filter unit for a mixing apparatus comprising: a hydrophilic filterconfigured to receive a fluid including a liquid, gas, and foamcomprised of the liquid containing trapped gas, the hydrophilic filterfurther configured to sterilize the liquid; a defoaming deviceconfigured to receive the gas, the foam, and some of the liquid from thehydrophilic filter, the defoaming device further configured to releaseat least some of the gas from the foam; and a hydrophobic vent filterconfigured to receive the gas from the defoaming device, the hydrophobicvent filter further comprising a vent and a membrane configured toseparate an interior of the filter unit from an exterior of the filterunit, the gas being vented from the filter unit by flowing across themembrane and out of the vent.
 8. The filter unit of claim 7, wherein thehydrophobic vent filter is configured to receive some of the liquid fromthe defoaming device.
 9. The filter unit of claim 7, wherein thedefoaming device contains a defoaming substance configured to releasethe at least some of the gas from the foam.
 10. The filter unit of claim9, wherein the defoaming substance comprises stainless steel shavings.11. The filter unit of claim 7, wherein the hydrophobic vent filter isat least partially composed of at least one of polytetrafluoroethyleneor polyvinylidene fluoride.
 12. The filter unit of claim 7, wherein thehydrophilic filter is at least partially composed of a polyethersulfone.13. The filter unit of claim 7, wherein the hydrophobic vent filterfurther comprises a hollow cylindrical filter element disposed within acylindrical filter capsule, the filter capsule comprising the vent andthe filter element comprising the membrane; and wherein the filterelement is coupled to the filter capsule such that gas is vented fromthe filter unit by flowing across the membrane into a hollow center ofthe filter element and out of the vent.
 14. The filter unit of claim 7,wherein the hydrophilic filter comprises a hollow cylindrical filterelement disposed within a cylindrical filter capsule, the filter capsulecomprising an outlet port and the filter element comprising a secondmembrane configured to sterilize the liquid; and wherein the filterelement is coupled to the filter capsule such that the liquid isevacuated from the filter unit by flowing across the second membraneinto a hollow center of the filter element and out of the outlet port.15. A method of filtering a solution comprising: receiving, at a filterunit comprised of a hydrophilic filter, a defoaming device, and ahydrophobic vent filter, a fluid including a liquid, gas, and foamcomprised of the liquid containing trapped gas; directing the gas andfoam to the defoaming device, wherein the defoaming device is configuredto release at least some of the gas from the foam; venting the gasacross a membrane and out of a vent of the hydrophobic vent filter, themembrane configured to separate an interior of the filter unit from anexterior of the filter unit; sterilizing the liquid by the hydrophilicfilter; and evacuating the sterilized liquid from the filter unit. 16.The method of claim 15, wherein the hydrophobic vent filter isconfigured to receive some of the liquid.
 17. The method of claim 15,wherein the defoaming device contains a defoaming substance configuredto release the at least some of the gas from the foam.
 18. The method ofclaim 15, wherein the hydrophobic vent filter is at least partiallycomposed of at least one of polytetrafluorethylene or polyvinylidenefluoride.
 19. The method of claim 15, wherein the hydrophobic ventfilter further comprises a hollow cylindrical filter element disposedwithin a cylindrical filter capsule, the filter capsule comprising thevent and the filter element comprising the membrane; and wherein ventingthe gas comprises venting the gas across the membrane into a hollowcenter of the filter element and out of the vent.
 20. The method ofclaim 15, wherein the hydrophilic filter comprises a hollow cylindricalfilter element disposed within a cylindrical filter capsule, the filtercapsule comprising an outlet port and the filter element comprising asecond membrane configured to sterilize the liquid; wherein sterilizingthe liquid comprises flowing the liquid across the membrane into ahollow center of the filter element; and wherein evacuating thesterilized liquid comprises evacuating the liquid out of the outletport.